Apolipoprotein AI (apo AI) is the most abundant protein in plasma high density lipoproteins (HDL). In addition to having a structural function, it is the physiologic cofactor of lecithin: cholesterol acyltransferase (LCAT). In tissue culture small apo AI-containing particles (pre-beta LpAI) have been found to be the primary acceptors of cell membrane cholesterol. In humans the rate of synthesis of apo AI is a partial determinant of plasma HDL cholesterol concentration (conc), and genetic defects leading to absence of apo AI produce severe premature atherosclerosis. Such observations suggest that apo AI production rate may be a major determinant of reverse cholesterol transport (RCT) and atherogenesis. Other evidence has suggested that apo AI may facilitate the catabolism of chylomicrons and very low density lipoproteins (VLDL). In order to test these hypotheses, human apo AI will be infused intravenously (i.v.) into otherwise healthy hypoalphalipoproteinemic humans in amounts sufficient to raise the plasma apo AI conc. Effects on RCT will be studied by examination of changes in: (a) the cholesterol contents of biopsied adipose tissue and skeletal muscle; (b) the compositions and cholesterol specific radioactivities of lipoproteins in plasma and peripheral lymph; (c) biliary cholesterol secretion; and (d) fecal bile acid excretion. Effects on catabolism of triglyceride-rich lipoproteins will be studied by examination of changes in: (a) the extent of postprandial lipemia after a standardized oral fat load; (b) VLDL apo B100 metabolism, quantified from the rate of incorporation of i.v. infused deuterated or [13C] leucine; and (c) the activities of lipoprotein lipase in adipose tissue and skeletal muscle biopsies. Control studies will be carried out using human albumin infusions. The outcome of these studies will more clearly define the role of apo AI in lipid transport. If a significant effect on RCT is demonstrated, this might lead to the development of a method for inducing the regression of atherosclerosis in humans.